It was previously demonstrated that antinociception elicited by morphine can be reduced by either FMRF-NH2, injected intraventricularly or intrathecally, or CCK-8-S04, injected intrathecally. Proglumide, a CCK receptor blocker, antagonized the antiopiate activity of CCK-8-S04 as expected and surprisingly also blocked the antiopiate activity of FMRF-NH2. The naturally occurring FMRF-NH2 immunoreactive material is different from authentic FMRF-NH2. In order to assess the role of endogenous FMRF-NH2 immunoreactivity and CCK-8-S04 in opiate action, the effects of proglumide and FMRF-NH2 antibody on opiate antinociception was studied. Both proglumide and IgG, isolated from FMRF-NH2 antiserum, were found to potentiate the morphine analgesia and also lessen the development of acute morphine tolerance induced by repeated injections of morphine at 2 hour intervals in rats. In further searching for interaction between FMRF-NH2 and morphine, it was found that 1) morphine, infused through the subarachnoidal space of spinal cords, induced FMRF-NH2-IR release and 2) opiate receptor of rat brain as measured by radioactive dihydromorphine was altered by FMRF-NH2. The results taken together suggest an important role for FMRF-NH2-IR in opiate antinociception. The role of FMRF-NH2-IR in chronic morphine tolerance will be further investigated.